3) It also has an antithrombotic action, mediated through
inhibition of platelet activation, which has been shown to be
useful in secondary prophylaxis following myocardial infarction,
and in patients with unstable angina and cerebral transient
ischaemic attacks.

4.2 Posology and method of administration

Posology

Adults including elderly: 1-2 tablets (300-600mg) every 3-4 hours as required, to a maximum
of 12 tablets (3.6g) daily in divided doses.

Children: Do not give to children aged under 16 years, unless specifically
indicated (e.g. for Kawasaki's disease).

Antithrombotic action: For its antithrombotic effect following myocardial infarction,
transient ischaemic attack, or in patients with unstable angina,
the recommended dose is 300mg daily.

Method of Administration

For oral administration.

4.3 Contraindications

Aspirin should not be taken by patients with the following
conditions:

• Known hypersensitivity to aspirin, other ingredients in the
product, other salicylates or non-steroidal anti-inflammatory drugs
(a patient may have developed anaphylaxis, angioedema, asthma,
rhinitis or urticaria induced by aspirin or other NSAIDs).

There is a possible association between aspirin and Reye's Syndrome
when given to children. Reye's syndrome is a very rare disease,
which affects the brain and liver, and can be fatal. For this
reason aspirin should not be given to children aged under 16 years,
unless on the advice of a doctor e.g Kawasaki's Syndrome

Aspirin should be used with caution in patients with:

• Acetylsalicylic acid may promote bronchospasm and asthma attacks
or other hypersensitivity reactions. Risk factors are existing
asthma, hay fever, nasal polyps or chronic respiratory diseases.
The same applies for patients who also show allergic reaction to
other substances (e.g. with skin reactions, itching or urticaria).

• Acetylsalicylic acid should be used with caution in patients with
moderately impaired renal or hepatic function (contraindicated if
severe), or in patients who are dehydrated since the use of NSAIDs
may result in deterioration of renal function. Liver function tests
should be performed regularly in patients presenting slight or
moderate hepatic insufficiency.

• There is an increased risk of haemorrhage particularly during or
after operative procedures (even in cases of minor procedures, e.g.
tooth extraction). Use with caution before surgery, including tooth
extraction. Temporary discontinuation of treatment may be
necessary.

• systemic lupus erythematosus and other connective tissue
disorders (hepatic and renal function may be impaired in these
conditions)

• thyrotoxicosis (may be exacerbated by large doses of salicylates)

• Elderly patients are particularly susceptible to the adverse
effects of NSAIDs, including acetylsalicylic acid especially
gastrointestinal bleeding and perforation which may be fatal (see
section 4.2). Where prolonged therapy is required, patients should
be reviewed regularly.

• Before commencing long-term aspirin therapy for the management of
cardiovascular or cerebrovascular disease patients should consult
their doctor who can advise on the relative benefits versus the
risks for the individual patient.

• Acetylsalicylic acid is not recommended during menorrhagia where
it may increase menstrual bleeding.

• Acetylsalicylic acid is to be used with caution in cases of
hypertension and when patients have a past history of gastric or
duodenal ulcer or haemorrhagic episodes or are undergoing therapy
with anticoagulants

• Patients should report any unusual bleeding symptoms to their
physician. If gastrointestinal bleeding or ulceration occurs the
treatment should be withdrawn

• Serious skin reactions, including Steven-Johnsons syndrome, have
rarely been reported in association with the use of acetylsalicylic
acid (see section 4.8). Acetylsalicylic acid should be discontinued
at the first appearance of skin rash, mucosal lesions, or any other
sign of hypersensitivity.

• Concomitant treatment with acetylsalicylic acid and other drugs
that alter haemostasis (i.e. anticoagulants such as warfarin,
thrombolytic and antiplatelet agents, anti-inflammatory drugs and
selective serotonin reuptake inhibitors) is not recommended, unless
strictly indicated, because they may enhance the risk of
haemorrhage (see section 4.5). If the combination cannot be
avoided, close observation for signs of bleeding is recommended.

• Caution should be advised in patients receiving concomitant
medications which could increase the risk of ulceration, such as
oral corticosteroids, selective serotonin-reuptake inhibitors and
deferasirox (see section 4.5).

• The risk of hypoglycaemic effect with sulfonylureas and insulins
may be potentiated with acetylsalicylic acid taken at over dosage
(see section 4.5).

• Where analgesics are used long-term (>3 months) with
administration every two days or more frequently, headache may
develop or worsen. Headache induced by overuse of analgesics (MOH
medication-overuse headache) should not be treated by dose
increase. In such cases, the use of analgesics should be
discontinued in consultation with the doctor.

Acetylsalicylic acid is not suitable for use as an
anti-inflammatory/analgesic/ antipyretic

The following warnings are on the OTC product labelling:

• Do not take if you have a stomach ulcer

• If symptoms persist for more than 3 days, consult your doctor

• Medicines should not be taken in pregnancy without consulting
your doctor

• Keep this medicine out of the sight and reach of children

• Do not give to children aged under 16 years, unless on the advice
of a doctor.

4.5 Interaction with other medicinal products and other forms of
interaction

The following drug interactions should be considered when
prescribing aspirin:

• Analgesics - avoid concomitant administration of other
salicylates or other NSAIDs (including topical formulations) as
increased risk of side effects.

• Ototoxic medicine (eg vancomycin) - potential for ototoxicity increased. Hearing loss
may occur and may progress to deafness even after discontinuation
of the medication. Effects may be reversible but are usually
permanent.

• Varicella vaccine - Vaccine recipients should avoid use of
salicylates for 6 weeks after vaccination with varicella vaccine as
Reye's syndrome has been reported following use of salicylates
during wild-type varicella infection (see section 4.4).

• Ginkgo Biloba – possible increase in risk of bleeding.

Contraindicated combinations

Methotrexate (used at doses >15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, enhance
haematological toxicity of methotrexate due to the decreased renal
clearance of methotrexate by acetylsalicylic acid. Therefore, the
concomitant use of methotrexate (at doses >15 mg/week) with
acetylsalicylic acid is contraindicated (see section 4.3).

Not recommended combinations

Uricosuric agents, e.g. probenecid

Salicylates reverse the effect of probenecid. The combination
should be avoided.

Combinations requiring precautions for use or to be taken into
account

Anticoagulants e.g. coumarin, heparin, warfarin

Increased risk of bleeding due to inhibited thrombocyte function,
injury of the duodenal mucosa and displacement of oral
anticoagulants from their plasma protein binding sites. The
bleeding time should be monitored (see section 4.4).

Acetylsalicylic acid impairs the renal excretion of digoxin and
lithium, resulting in increased plasma concentrations. Monitoring
of plasma concentrations of digoxin and lithium is recommended when
initiating and terminating treatment with acetylsalicylic acid.
Dose adjustment may be necessary

Diuretics and antihypertensives

NSAIDs may decrease the antihypertensive effects of diuretics and
other antihypertensive agents. As for other NSAIDs concomitant
administration with ACE-inhibitors increases the risk of acute
renal insufficiency.

Diuretics: Risk of acute renal failure due to the decreased
glomerual filtration via decreased renal prostaglandin synthesis.
Hydrating the patient and monitoring renal function at the start of
the treatment is recommended.

Carbonic anhydrase inhibitors (acetazolamide)

May result in severe acidosis and increased central nervous system
toxicity

Systemic corticosteroids

The risk of gastrointestinal ulceration and bleeding may be
increased when acetylsalicylic acid and corticosteroids are
co-administered (see section 4.4).

Methotrexate (used at doses <15 mg/week):

The combined drugs, methotrexate and acetylsalicylic acid, may
increase haematological toxicity of methotrexate due to decreased
renal clearance of methotrexate by acetylsalicylic acid. Weekly
blood count checks should be done during the first weeks of the
combination. Enhanced monitoring should take place in the presence
of even mildly impaired renal function, as well, as in elderly.

Other NSAIDs

Increased risk of ulcerations and gastrointestinal bleeding due to
synergistic effects.

Ciclosporin, tacrolimus

Concomitant use of NSAIDs and ciclospoin or tacrolimus may increase
the nephrotoxic effect of ciclosporin and tacrolimus. The renal
function should be monitored in case of concomitant use of these
agents and acetylsalicylic acid.

Valproate

Acetylsalicylic acid has been reported to decrease the binding of
valproate to serum albumin, thereby increasing its free plasma
concentrations at steady state.

Phenytoin

Salicylate diminishes the binding of phenytoin to plasma albumin.
This may lead to decreased total phenytoin levels in plasma, but
increased free phenytoin fraction. The unbound concentration, and
thereby the therapeutic effect, does not appear to be significantly
altered.

Alcohol

Concomitant administration of alcohol and acetylsalicylic acid
increases the risk of gastrointestinal bleeding.

Ibuprofen

Experimental data suggest that ibuprofen may inhibit the effect of
low dose acetylsalicylic acid on platelet aggregation when they are
dosed concomitantly. However, the limitations of these data and the
uncertainties regarding extrapolation of ex vivo data to the
clinical situation imply that no firm conclusions can be made for
regular ibuprofen use, and no clinically relevant effect is
considered to be likely for occasional ibuprofen use (see section
5.1).

There is insufficient clinical experience regarding the use of
doses above 100 mg/day up to 500 mg/day. Therefore, the
recommendations below for doses of 500 mg/day and above apply also
for this dose range.

Doses of 500 mg/day and above:

Inhibition of prostaglandin synthesis may adversely affect the
pregnancy and/or the embryo/foetal development. Data from
epidemiological studies suggest an increased risk of miscarriage,
and of cardiac malformation and gastroschisis after use of a
prostaglandin synthesis inhibitor in early pregnancy. The absolute
risk for cardiovascular malformation was increased from less than
1%, up to approximately 1.5 %. The risk is believed to increase
with dose and duration of therapy. In animals, administration of a
prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post-implantation loss and embryo-foetal
lethality. In addition, increased incidences of various
malformations, including cardiovascular, have been reported in
animals given a prostaglandin synthesis inhibitor during the
organogenetic period. During the first and second trimester of
pregnancy, acetylsalicylic acid should not be given unless clearly
necessary. If acetylsalicylic acid is used by a woman attempting to
conceive, or during the first and second trimester of pregnancy,
the dose should be kept as low and duration of treatment as short
as possible.

Regular or high dose use of salicylates late in pregnancy may
result in:

- kernicterus in jaundiced neonates

During the third trimester of pregnancy, all prostaglandin
synthesis inhibitors may expose the foetus to:

Consequently, acetylsalicylic acid at doses of 100 mg/day and
higher is contraindicated during the third trimester of pregnancy.

Lactation

Low quantities of salicylates and of their metabolites are excreted
into the breast milk. Adverse effects for the infant have not been
reported up to now. However, aspirin should be avoided during
lactation because of the possible risk of Reye's syndrome. In cases
of long-term use and/or administration of higher doses,
breastfeeding should be discontinued. Regular use of high doses of
aspirin could impair platelet function and produce
hypoprothrombinaemia in the infant neonatal vitamin K stores are
low.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines
have been performed with Acetylsalicylic acid.

Based on the pharmacodynamic properties and the side effects of
acetylsalicylic acid, no influence on the reactivity and the
ability to drive or use machines is expected.

4.8 Undesirable effects

Side effects are grouped on the basis of System Organ Class. Within
each system organ class the frequencies are defined as: very common
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to
<1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000) and not known (cannot be estimated from the
available data)

Blood and lymphatic system disorders

Common:

Increased bleeding tendencies.

Rare:

Thrombocytopenia, agranulocytosis, aplastic anaemia.

Not known:

Cases of bleeding with prolonged bleeding time such as epistaxis,
gingival bleeding. Symptoms may persist for a period of 4–8 days
after acetylsalicylic acid discontinuation. As a result there may
be an increased risk of bleeding during surgical procedures.

Existing (haematemesis, melaena) or occult gastrointestinal
bleeding, which may lead to iron deficiency anaemia (more common at
higher doses).

Salicylism – (mild chronic salicylate intoxication may occur after
repeated administration of large doses, symptoms include dizziness,
tinnitus, deafness, sweating, nausea, vomiting, headache and mental
confusion, and may be controlled by reducing the dose)

Children

Aspirin may be associated with the development of Reye's Syndrome
(encephalopathy and hepatic failure) in children presenting with an
acute febrile illness.

4.9 Overdose

Although considerable inter-individual variations are involved, it
can be considered that the toxic dose is about 200 mg/kg in adults
and 100 mg/kg in children. The lethal dose of acetylsalicylic acid
is 25-30 grams. Salicylate poisoning is usually associated with
plasma concentrations >350 mg/L (2.5 mmol/L). Plasma
concentrations above 500 mg/l in adults and 300 mg/l in children
generally cause severe toxicity. Most adult deaths occur in
patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single
doses less than 100 mg/kg are unlikely to cause serious poisoning.

Plasma salicylate concentrations should be measured urgently for
patients who are thought to have ingested more than 125 mg/kg of
aspirin. The sample should be taken at least 2 hours (symptomatic
patients) or 4 hours (asymptomatic patients) after ingestion, since
it may take several hours for peak plasma concentrations to occur
and up to 12 hours for enteric-coated preparations. A repeat sample
should be taken in ALL symptomatic patients and those with
concentrations greater than 500 mg/L after a further 2 hours
because of the possibility of continuing absorption. Under these
circumstances, measurements should be repeated every 3 hours until
concentrations are falling.

Symptoms

Common features include vomiting, dehydration, tinnitus, vertigo,
deafness, sweating, warm extremities with bounding pulses,
increased respiratory rate and hyperventilation. Some degree of
acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or
high arterial pH (normal or reduced hydrogen ion concentration) is
usual in adults and children over the age of four years. In
children aged four years or less, a dominant metabolic acidosis
with low arterial pH (raised hydrogen ion concentration) is common.
Acidosis may increase salicylate transfer across the blood brain
barrier.

Central nervous system features including confusion, restlessness,
hallucinations, disorientation, coma, cardiovascular collapse,
respiratory arrest and convulsions are less common in adults than
in children.

Management

If a toxic dose has been ingested, hospital admission is required

Give activated charcoal if an adult presents within one hour of
ingestion of more than 250 mg/kg. The plasma salicylate
concentration should be measured, although the severity of
poisoning cannot be determined from this alone and the clinical and
biochemical features must be taken into account. Elimination is
increased by urinary alkalinisation, which is achieved by the
administration of 1.26% sodium bicarbonate. The urine pH should be
monitored. Correct metabolic acidosis with intravenous 8.4% sodium
bicarbonate (first check serum potassium). Forced diuresis should
not be used since it does not enhance salicylate excretion and may
cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and
should be considered in patients with plasma salicylate
concentrations >700 mg/L (5.1 mmol/L), or lower concentrations
associated with severe clinical or metabolic features. Patients
under ten years or over 70 have increased risk of salicylate
toxicity and may require dialysis at an earlier stage.

Other symptoms to be treated symptomatically.

5. Pharmacological properties

5.1 Pharmacodynamic properties

ATC code: N02BA01

Aspirin is an anti-inflammatory analgesic and antipyretic.

Aspirin is analgesic, anti-inflammatory, antipyretic and an
inhibitor of platelet aggregation. It prolongs the bleeding time.
It inhibits fatty acid cyclo-oxygenase by acetylation of the active
site of the enzyme, and most of its pharmacological effects are due
to inhibition of the formation of cyclo-oxygenase products
including thromboxanes, prostaglandins and prostacyclin. The effect
on platelets is cumulative over their 8-day life span because they
have no capacity to resynthesize the cyclo-oxygenase enzyme.
Aspirin has an active metabolite (salicylate) which, in addition to
possessing some anti-inflammatory properties in its own right, also
has important effects on respiration, acid-base balance and the
stomach. Salicylates stimulate respiration by a direct effect on
the medulla, and at high concentrations, uncouple oxidative
phosphorylation in muscle, increasing oxygen consumption and carbon
dioxide production. Hyperventilation causes respiratory alkalosis
which is compensated by renal excretion of bicarbonate. When large
toxic doses of salicylate are ingested and carbohydrate metabolism
is deranged, lactic and pyruvic acids accumulate and renal function
is impaired, resulting in metabolic acidosis. Salicylates have a
direct irritant effect on the gastric mucosa and further predispose
to ulceration by inhibiting synthesis of vasodilator and
cytoprotective prostaglandins.

Experimental data suggest that ibuprofen may inhibit the effect of
low dose acetylsalicylic acid on platelet aggregation when they are
dosed concomitantly. In one study, when a single dose of ibuprofen
400mg was taken within 8 hours before or within 30 minutes after
immediate release acetylsalicylic acid dosing (81mg), a decreased
effect of ASA on the formation of thromboxane or platelet
aggregation occurred. However, the limitations of these data and
the uncertainties regarding extrapolation of ex vivo data to the
clinical situation imply that no firm conclusions can be made for
regular ibuprofen use, and no clinically relevant effect is
considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic properties

Following oral administration, absorption of non-ionised aspirin
occurs in the stomach and intestine. Some aspirin is hydrolysed
salicylate in the gut wall. After absorption aspirin is rapidly
converted to salicylate but during the first twenty minutes
following oral administration, aspirin is the predominant form of
the drug in the plasma. Aspirin is bound to plasma proteins and is
widely distributed. Plasma-aspirin concentrations decline rapidly
(half-life 15-20 minutes) as plasma salicylate concentrations
increase. Salicylates are extensively bound to plasma proteins and
are rapidly distributed to all body parts. Salicylates appear in
breast milk and cross the placenta. Salicylate is mainly eliminated
by hepatic metabolism; the metabolites include salicyluric acid,
salicyl phenolic glucuronide, salicylic acyl glucuronide, gentisic
acid, and gentisuric acid. Following a 325mg aspirin dose,
elimination is a first-order process and the serum-salicylate
half-life is about two to three hours; at high aspirin doses, the
half-life increases to fifteen to thirty hours. Salicylate is also
excreted unchanged in the urine; the amount excreted by this route
increases with increasing dose and also depends on urinary pH,
about 30% of a dose being excreted in alkaline urine compared with
2% of a dose in acidic urine. Renal excretion involves glomerular
filtration, active renal tubular secretion, and passive tubular
reabsorption. Salicylates are removed by haemodialysis.

The product containers are rigid injection moulded polypropylene or
injection blow-moulded polyethylene containers with polyfoam wad or
polyethylene ullage filler and snap-on polyethylene lids; in case
any supply difficulties should arise the alternative is amber glass
containers with screw caps and polyfoam wad or cotton wool. An
alternative closure for polyethylene containers is a polypropylene,
twist on, push down and twist off child-resistant, tamper-evident
lid.

Product may also be supplied in bulk packs, for reassembly purposes
only, in polybags contained in tins, skillets or polybuckets filled
with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the
proposed marketing containers.